Cellular Actions of Petit Mal Anticonvulsants: Implication of Thalamic Low-Threshold Calcium Current in Generation of Spike-Wave Discharge

  • D. A. Coulter
  • J. R. Huguenard
  • D. A. Prince


Typical absence or petit mal seizures are associated with large amplitude, synchronized, low-frequency spike-wave discharges (SWD) on the electroencephalogram. Extracellular recordings both thalamic and cortical neuronal activity during SWDs in animal models of petit mal (Gloor and Fariello, 1988; Vergnes, et al., 1987) and EEG and depth recordings in the thalamus and cortex of humans during petit mal attacks (Williams, 1953) have demonstrated that these 3/second rhythms are due to an underlying thalamocortical oscillatory interaction. Other types of thalamocortical oscillatory behavior, such as sleep spindles, involve a complex interaction between synaptic excitatory and inhibitory connections and intrinsic membrane conductances in both thalamic and cortical areas (Steriade and Deschênes, 1984; Steriade and Llinás, 1988). Similar rhythmic activity can be recorded in the isolated thalamus (Morison and Bassett, 1945). A low-threshold calcium conductance, particularly prominent in thalamic neurons, has been shown to be of primary importance in the generation of oscillatory behavior in the thalamus (Jahnsen and Llinás, 1984a,b; Deschênes et al., 1982), including that which occurs during sleep spindles (Steriade and Deschênes, 1984; Steriade and Llinás, 1988). It has been hypothesized for decades that the thalamocortical mechanisms involved in the generation of recruiting responses and spindle rhythms are also involved in the generation of SWD (Jasper and Droogleever-Fortuyn, 1946). In addition, there is a significant correlation between the occurrence of sleep spindles and SWD in petit mal epileptics (Kella-way, 1985), as well as during the induction of SWD in a feline penicillin model of generalized SWD (Gloor and Fariello, 1988), which suggests a potential similarity in the underlying mechanisms. We therefore hypothesized that the low-threshold calcium conductance in thalamic neurons might be important in the generation of SWD and petit mal attacks. One of the most selective drugs for the control of petit mal epilepsy is ethosuximide (Brown et al., 1975). However, no cellular mechanism of action for this agent, consistent with its clinical utility, has been demonstrated. We reasoned that one mechanism by which ethosuximide might control SWD would be to reduce the calcium conductance underlying low-threshold calcium spikes in thalamic neurons, thereby dampening the thalamocortical oscillation underlying (and generating) petit mal attacks. To investigate potential cellular mechanisms of action of ethosuximide, and to provide further support for our hypothesis concerning the importance of low-threshold calcium spikes in the generation of SWD, we examined the effects of ethosuximide on current- and voltage-clamped thalamic neurons in vitro. Our findings suggest that the low-threshold calcium conductance in thalamic neurons is an important cellular event in the generation of SWD. In addition to demonstrating a cellular mechanism for the action of ethosuximide and other specific petit mal anticonvulsants, our data also provide a new testable hypothesis concerning potential crucial factors in the pathogenesis of petit mal epilepsy.


Calcium Current Potassium Current Sleep Spindle Thalamic Neuron Repeatable Manner 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Brown, T.R., Dreifuss, F.E., Dyken, P.R., Goode, D.J., Penry, J.R., Porter, R.J., White, B.G., and White, P.T., 1975, Ethosuximide in the treatment of absence (petit mal) seizures. Neurology 25: 515–524.Google Scholar
  2. Chamberlain, H.R., Waddell, W.J., and Butler, T.C., 1965, A study of the product of demeth-ylation of trimethadione in the control of petit mal epilepsy. Neurology 15: 449–454.Google Scholar
  3. Crunelli, V., Haby, M., Jassik-Gerschenfeld, D., Leresche, N., and Pirchio, M. 1988, Cl-and K+-dependent inhibitory postsynaptic potentials evoked by interneurones of the rat lateral geniculate nucleus. J. Physiol. (Lond.) 399: 153–176.Google Scholar
  4. Deschênes, M., Roy, J.P., and Steriade, M., 1982, Thalamic bursting mechanism: An inward slow current revealed by membrane hyperpolariza-tion. Brain Res. 239: 289–293.CrossRefGoogle Scholar
  5. Ferrendelli, J.A., and Kupferberg, H.J., 1980, Suc-cinimides. In: Glaser, G.H., Penry, J.K., and Woodbury, D.M. (eds.): Antiepileptic Drugs: Mechanisms of Action, Raven Press, New York, pp. 587–596Google Scholar
  6. Gloor, P., and Fariello, R.G., 1988, Generalized epilepsy: Some of its cellular mechanisms differ from those of focal epilepsy. TINS 11: 63–68.Google Scholar
  7. Jahnsen, H., and Llinás, R., 1984a, Electrophysiological properties of guinea-pig thalamic neurones: An in vitro study. J. Physiol. (Lond.) 349: 205–226.Google Scholar
  8. Jahnsen, H., and Llinás, R., 1984b, Ionic basis for the electroresponsiveness and oscillatory properties of guinea-pig thalamic neurones in vitro. J. Physiol. (Lond.) 349: 227–247.Google Scholar
  9. Jasper, H.H., and Droogleever-Fortuyn, J., 1946, Experimental studies of the functional anatomy of petit mal epilepsy. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 26: 272–98.Google Scholar
  10. Jones, E.G., 1985, The Thalamus. Plenum Press, New York.Google Scholar
  11. Kellaway, P., 1985, Sleep and epilepsy. Epilepsia 26: S15–S30.CrossRefGoogle Scholar
  12. King, G.A., 1979, Effects of systemically applied GABA agonists and antagonists on wave-spike ECoG activity in the rat. Neuropharmacology 18: 47–55.CrossRefGoogle Scholar
  13. Löscher, W., Nau, H., and Siemes, H., 1988, Penetration of valproate and its metabolites into cerebrospinal fluid of children with epilepsy. Epilepsia 29: 311–316.CrossRefGoogle Scholar
  14. Macdonald, R.L., and Bergey, G.K., 1979, Valproic acid augments GABA-mediated postsynaptic inhibition in cultured mammalian neurons. Brain Res. 170: 558–562.CrossRefGoogle Scholar
  15. McLean, M.J., and Macdonald, R.L., 1986, Sodium valproate, but not ethosuximide, produces use-and voltage-dependent limitation of high frequency repetitive firing of action potentials in mouse central neurons in cell culture. J. Pharmacol. Exp. Ther. 237: 1001–1011.Google Scholar
  16. Miller, J.W., Hall, C.M., Holland, K., and Ferrendelli, J.A., 1988, GABAergic mechanisms regulating seizures and arousal in the midline thalamus. Epilepsia 29: 659.Google Scholar
  17. Morison, R.S., and Bassett, D.L., 1945, Electrical activity of the thalamus and basal ganglia in decorticate cats. J. Neurophysiol. 8: 309–314.Google Scholar
  18. Steriade, M., and Deschênes, M., 1984, The thalamus as a neuronal oscillator. Brain Res. Rev. 8: 1–63.CrossRefGoogle Scholar
  19. Steriade, M., and Llinás, R.R., 1988, The functional states of the thalamus and the associated neuronal interplay. Physiol. Rev. 68: 649–742.Google Scholar
  20. Thomson, A.M., 1988, Inhibitory postsynaptic potentials evoked in thalamic neurons by stimulation of the reticularis nucleus evoke slow spikes in isolated rat brain slices-I. Neuroscience 25: 491–502.CrossRefGoogle Scholar
  21. Twombly, D.A., Yoshii, M., and Narahashi, T., 1988, Mechanisms of calcium channel block by Phenytoin. J. Pharmacol. Exp. Ther. 246: 189–195.Google Scholar
  22. Vergnes, M., Marescaux, C., Micheletti, G., Depaulis, A., Rumbach, L., and Wärter, J.M., 1984, Enhancement of spike and wave discharges by GABAmimetic drugs in rats with spontaneous petit-mal-like epilepsy. Neurosci. Lett. 44: 91–94.CrossRefGoogle Scholar
  23. Vergnes, M., Marescaux, C., Depaulis, A., Micheletti, G., and Warter, J.M., 1987, Spontaneous spike and wave discharges in thalamus and cortex in a rat model of genetic petit mal-like seizures. Exp. Neurol. 96: 127–136.CrossRefGoogle Scholar
  24. Williams, D., 1953, A study of thalamic and cortical rhythms in petit mal. Brain 76: 50–69.CrossRefGoogle Scholar
  25. Yaari, Y., Hamon, B., and Lux, H.D., 1987, Development of two types of calcium channels in cultured mammalian hippocampal neurons. Science 235: 680–682.CrossRefGoogle Scholar

Copyright information

© Birkhäuser Boston, Inc. 1990

Authors and Affiliations

  • D. A. Coulter
  • J. R. Huguenard
  • D. A. Prince

There are no affiliations available

Personalised recommendations